Thoracic aortic aneurysm and/or dissection (TAA/TAD) is the 16th cause of death in USA. It differs from the other common form of aneurysm - abdominal aortic aneurysm (AAA) both clinically and pathologically. Little data, however, are available specifically for the pathogenesis of TAA/TAD. We hypothesize that genetic variants contribute significantly to the sporadic TAA and TAD. This genetically determined susceptibility is modifiable or conditional on the presence of other factors including cigarette smoking, hypertension and inflammation, which directly interact with aortic wall integrity and remodeling. We will employ a targeted candidate gene approach and determine representatively distributed single nucleotide polymorphisms (SNPs) in 800 chronic TAA patients, 400 chronic co-existing TAA and TAD patients, 200 acute TAD patients and 800 healthy controls of age- gender- matched to TAA patients. We will measure selected 1500 SNPs from 138 genes (approximately 10 SNPs/gene) with their products regulating arterial wall ECM equilibrium. Specifically, we will (1) determine genetic variants that may be associated with the clinical endpoints of the development and progression of thoracic aortic aneurysm (TAA) and dissection (TAD);(2) investigate the genetic variants that may be associated with histopathological endpoints in aortic wall;(3) fine-mapping and re-sequencing the candidate genes in which SNPs have been found to be associated with clinical diseases or pathological phenotypes. We will determine expression profiles of these candidate genes and related to genotypes of the significant SNPs as the first step in defiining functional SNPs. Using maximum likelihood based statistical models, we will identify genes and their variants that are associated with clinical diagnosis of TAA/TAD, pathological changes in aortic wall and biochemical intermediate phenotypic traits. This project will document risk factors predicting TAA/TAD, genes and their variants predisposing TAA/TAD, genotype-environmental specific susceptibility to TAA/TAD development and progression. Our study is novel in exploring the genetic associations with three unique phenotypic endpoints: clinical, histopathological and biochemical. Our project is feasible since we will use a welldeveloped population genetic model to investigate the novel hypothesis. Our study will lead to discoveries that can be potentially used clinically for diagnosis, prognosis and guidance for treatment strategies.